Mechanisms of Parp inhibitor-induced bone marrow toxicities

PROJECT SUMMARY Poly-(ADP ribose) polymerase (PARP) inhibitors as a drug class are considered one of the great success stories of Precision Medicine with Food and Drug Administration drug approvals accumulating for growing proportions of patients with diverse cancer types. As well, preclinical studies are investigating their use in a multitude of non-malignant diseases. These drugs inhibit multiple PARP enzymes at once, some of which are critical enzymes for sensing and coordinating repair of several types of DNA damage. Further, these drugs trap the PARP1 enzyme onto DNA, resulting in a DNA double strand break to resolve this lesion. Thus, by design, these drugs increase DNA damage in cells, raising concern that they could be toxic to or even mutate normal cells that rely on PARP enzymes for their functions. Thus, clinical trial and drug safety databases showing serious bone marrow adverse effects, including severe, and sometimes irreversible lowering of the blood counts, and an increased risk of deadly therapy-related bone marrow cancers suggest that hematopoietic stem and progenitor cells are uniquely susceptible to PARP inhibitor effects. However, mechanism and causation are not yet clear. The long-term goal is to understand normal bone marrow function and if patients with germline or acquired mutations in their bone marrow cells are uniquely susceptible to the adverse effects of specific exposures. The central hypothesis is that 1) PARP inhibitors, due to their ability to stall replication forks and cause double strand DNA breaks, impair hematopoietic stem and progenitor cell proliferation, resulting in decreased blood cell production from the most proliferative subsets more than others., and that 2) these PARP inhibitor effects mobilize long-term stem cells to help meet blood production demands and at the same time create a competitive environment in which stem cells with TP53 or other mutations are favored to outgrow wild- type, but ultimately predisposing patients to bone marrow failure or leukemia. The rationale for this project is that an ever-expanding group of patients are being treated with PARP inhibitors and many experience serious blood and bone marrow toxicities, including development of therapy-related blood cancers, but the mechanism and methods to prevent these serious toxicities are not known. Using mouse and human in vitro and in vivo models, we will test these hypotheses with the following specific aims: 1) Determine how PARP inhibitors disrupt normal hematopoiesis to cause cytopenias; and 2) Determine whether PARP inhibitors create a selective environment and unmask fitness differences in hematopoietic stem and progenitor cells with varying genotypes or are able to mutate these cells on their own. The research proposed in this application is innovative because it is the first study to determine how inhibiting multiple PARP enzymes simultaneously impacts normal hematopoiesis on a mechanistic level. This proposal is significant because it will allow identification of prevention strategies for safe PARP inhibitor use and of new drug targets for improving hematopoiesis via PARP enzyme manipulations.